Efficient stereoconservative synthesis of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines and intermediates thereto

Abstract

Stereoconservative method for preparation of an (R)- or (S)-isomer of the compound of the formula I with at least 95% optical purity ##STR1## wherein R 1 is a hydrogen atom, a saturated or unsaturated lower alkyl group, a cycloalkyl group, or a group (CH 2 ) m Ph wherein m is 0-3 and Ph is a substituted or unsubstituted phenyl group including 1) O,N-dialkylation, directly or stepwise of (R)- or (S)-proline 2) aminolysis 3) reduction to formation of the (R)- or (S)-isomer of the compound of the formula I, and new intermediates II and III in optical active form obtained by the reaction steps above and wherein R 2 is defined as R 1 above. ##STR2##

We claim: 
     
       1. A stereoconservative method for preparation of the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity ##STR18## wherein R 1  is a hydrogen atom, a lower alkyl, alkenyl or alkynyl group, a cycloalkyl group, or a group (CH 2 ) m  Ph where m is 0-3 and Ph is a substituted or unsubstituted phenyl group, which comprises treating (R)- or (S)-proline of the formula ##STR19## or a salt thereof with retention of the stereochemistry, by o-alkylation with R 2  CH 2  OH or R 2  CH 2  X wherein R 2  has the same definition as R 1  above and X is a halogen or a sulfonic acid residue to form the (R)- or (S)-isomer of an ester of the formula V ##STR20## or a salt thereof followed by N-alkylation with R 1  CH 2  X in the presence of a base in a suitable organic solvent or by reductive alkylation with R 1  CHO and a reducing agent, where R 1  and X are as defined above to form an ester of the formula II ##STR21## followed by aminolysis at a temperature below 100° C. to form the (R)- or (S)-isomer of an amide with the formula III ##STR22## followed by reduction of the amide of formula III to form the (R)- or (S)-isomer of a compound of formula I with at least 95% optical purity. 
     
     
       2. A stereoconservative method for preparation of the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity ##STR23## wherein R 1  is a hydrogen atom, a lower alkyl, alkenyl or alkynyl group, a cycloalkyl group, or a group (CH 2 ) m  Ph wherein m is 0-3 and Ph is a substituted or unsubstituted phenyl group, which comprises aminolysis at a temperature below 100° C. of the (R)- or (S)-isomer of an ester of the formula II ##STR24## wherein R 1  and R 2  are the same or different and are defined as R 1  above in an alcoholic ammonia solution in the presence of an anion catalyst to form the (R)- or (S)-isomer of an amide of the formula III ##STR25## followed by reduction of the amide to form the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity. 
     
     
       3. A stereoconservative method for preparation of the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity ##STR26## wherein R 1  is a hydrogen atom, a lower alkyl, alkenyl or alkynyl group, a cycloalkyl group, or a group (CH 2 ) m  Ph wherein m is 0-3 and Ph is a substituted or unsubstituted phenyl group, which comprises treating (R)- or (S)-proline of the formula ##STR27## or a salt thereof with retention of the stereochemistry, by direct O,N-dialkylation of (R)- or (S)-proline with R 1  CH 2  X, wherein X is a halogen or a sulfonic acid residue, and R 1  is as defined above, in the presence of a base in a suitable organic solvent, to form the (R)- or (S)-isomer of an ester of the formula II ##STR28## or a salt thereof wherein R 1  and R 2  are the same and defined as R 1  above, followed by aminolysis at a temperature below 100° C. to form the (R)- or (S)-isomer of an amide with the formula III ##STR29## where R 1  is defined as above, followed by reduction of the amide of formula III to form the (R)- or (S)-isomer of a compound of formula I with at least 95% optical purity. 
     
     
       4. A stereoconservative method for preparation of the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity ##STR30## wherein R 1  is a hydrogen atom, a lower alkyl, alkenyl or alkynyl group, a cycloalkyl group, or a group (CH 2 ) m  Ph wherein m is 0-3 and Ph is a substituted or unsubstituted phenyl group, which comprises treating (R)- or (S)-proline of the formula ##STR31## or a salt thereof with retention of the stereochemistry by N-alkylation with R 1  CH 2  X in the presence of a base in a suitable organic solvent or by reductive alkylation with R 1  CHO and a reducing agent wherein R 1  is as defined above and X is a halogen or a sulfonic acid residue to form the (R)- or (S)-isomer of a compound of the formula IV ##STR32## or a salt thereof followed by O-alkylation with R 2  CH 2  X in the presence of a base in a suitable organic solvent or esterification with R 2  CH 2  OH, where R 2  has the same definition as R 1  and X is as defined above, followed by aminolysis at a temperature below 100° C. of an ester of the formula II ##STR33## to form the (R)- or (S)-isomer of an amide with the formula III ##STR34## wherein R 1  is defined as above, followed by reduction of the amide of the formula III to form the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity. 
     
     
       5. A stereoconservative method for preparation of the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity ##STR35## wherein R 1  is a hydrogen atom, a lower alkyl, alkenyl or alkynyl group, a cycloalkyl group, or a group (CH 2 ) m  Ph wherein m is 0-3 and Ph is a substituted or unsubstituted phenyl group, which comprises treating (R)- or (S)-proline of the formula ##STR36## or a salt thereof with retention of the stereochemistry, by O-alkylation with R 2  CH 2  OH or R 2  CH 2  X, wherein R 2  has the same definition as R 1  above and X is a halogen or a sulfonic acid residue, of (R)- or (S)-proline to form the (R)- or (S)-isomer of an ester of the formula V ##STR37## where R 2  is a hydrogen atom, a lower alkyl, alkenyl or alkynyl group, a cycloalkyl group or a group (CH 2 ) m  Ph wherein m is 0-3 and Ph is a substituted or unsubstituted phenyl group, followed by aminolysis at a temperature below 100° C. to form the (R)- or (S)-isomer of the amide of the formula VI ##STR38## followed by N-alkylation of the amide of formula VI with R 1  CH 2  X in the presence of a base and in suitable organic solvent or by reductive alkylation with R 1  CHO and a reducing agent, where R 1  and X are as defined above, to form the (R)- or (S)-isomer of the compound of the formula III ##STR39## followed by reduction of the amide of formula III to form the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity. 
     
     
       6. A method according to any of claims 1, 2, 3, 4 or 5, wherein the aminolysis step is performed in an alcoholic ammonia solution in the presence of a cyanide ion as an anion catalyst. 
     
     
       7. A stereoconservative method for preparation of the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity ##STR40## wherein R 1  is a lower alkyl, alkenyl or alkynyl group, a cycloalkyl group, or a group (CH 2 ) m  Ph wherein m is 0-3 and Ph is an unsubstituted or substituted phenyl group, which comprises N-alkylation of the (R)- or (S)-isomer of the amide of the formula VI ##STR41## with R 1  CH 2  X, wherein X is a halogen or a sulfonic acid residue, in the presence of a base and in a suitable organic solvent or with R 1  CHO and a reducing agent to form the (R)- or (S)-isomer of an amide of the formula III ##STR42## followed by reduction of the amide of the formula III to form the (R)- or (S)-isomer of a compound of the formula I with at least 95% optical purity.